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Originally published In Press as doi:10.1074/jbc.M207825200 on October 22, 2002

J. Biol. Chem., Vol. 277, Issue 52, 50980-50984, December 27, 2002
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alpha -Synuclein Lowers p53-dependent Apoptotic Response of Neuronal Cells
ABOLISHMENT BY 6-HYDROXYDOPAMINE AND IMPLICATION FOR PARKINSON'S DISEASE*

Cristine Alves da Costa, Erwan Paitel, Bruno Vincent, and Frédéric CheclerDagger

From the Institut de Pharmacologie Moléculaire et Cellulaire du CNRS, UMR6097, 660 route des Lucioles, 06560 Valbonne, France

We have examined the influence of alpha -synuclein on the responsiveness of TSM1 neuronal cells to apoptotic stimulus. We show that alpha -synuclein drastically lowers basal and staurosporine-stimulated caspase 3 immunoreactivity and activity. This is accompanied by lower DNA fragmentation and reduced number of terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL)-positive neurons. Interestingly, alpha -synuclein also diminishes both p53 expression and transcriptional activity. We demonstrate that the antiapoptotic phenotype displayed by alpha -synuclein can be fully reversed by the Parkinson's disease-associated dopamine derivative 6-hydroxydopamine. Thus, 6-hydroxydopamine fully abolishes the alpha -synuclein-mediated reduction of caspase 3 activity and reverses the associated decrease of p53 expression. 6-Hydroxydopamine triggers thioflavin T-positive deposits in alpha -synuclein, but not mock-transfected TSM1 neurons, and drastically increases alpha -synuclein immunoreactivity. Altogether, we suggest that alpha -synuclein lowers the p53-dependent caspase 3 activation of TSM1 in response to apoptotic stimuli and we propose that the natural toxin 6-hydroxydopamine abolishes this antiapoptotic phenotype by triggering alpha -synuclein aggregation, thereby likely contributing to Parkinson's disease neuropathology.

* This work was supported by the center National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, and by Aventis Pharma.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 33-4-93-95-77-60; Fax: 33-4-93-95-77-08; E-mail: checler@ipmc.cnrs.fr.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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